1. Field of the Invention
The present invention relates generally to the field of diagnostic imaging. More particularly, it concerns a microscope that utilizes the interaction of light with tissues in many modalities to image morphology and biochemistry, thereby providing better delineation of tumors. Even more particularly, it concerns a miniaturized microscope capable of different imaging modalities such as optical sectioning, 3-D spectral fluorescence imaging, and reflectance imaging.
2. Description of Related Art
The American Cancer Society estimates that 1,220,100 people will have been diagnosed with cancer in 2000. In the same year, 552,200 persons were expected to succumb to cancer. Despite significant advances in treatment, early detection of cancer and its curable precursors remains the best way to ensure patient survival and quality of life.
Pre-cancers are characterized by morphologic and biochemical changes that include increased nuclear size, increased nuclear to cytoplasmic ratio, hyperchromasia, pleomorphism, angiogenesis, and increased metabolic rate. These changes currently can only be assessed through invasive biopsy. Early detection of curable pre-cancers has the potential to significantly lower cancer mortality and morbidity. Many visual exam procedures, such as colonoscopy and bronchoscopy, are routinely used to identify pre-malignant changes and early cancers. However, these techniques do not assess the microscopic and/or biochemical changes which are the hallmark of pre-cancer. Thus, these techniques' sensitivity and specificity are limited.
Early detection would be particularly beneficial in the treatment of several types of cancers. For instance, cancer of the oral cavity is usually not diagnosed until it is in an advanced stage. In the advanced stage, treatment is more disfiguring, expensive, and prone to failure. Thus, early detection of pre-cancer is the best method to improve patient quality of life and survival. Certain lesions in the oral cavity have been identified clinically to have the potential for malignant conversion. These include leukoplakia (white plaques) and erythroplakia (velvety, reddish lesions). Invasive biopsies are often required to confirm the presence of pre-cancer. Thus, despite the easy accessibility of the oral cavity to examination, there is no satisfactory mechanism to adequately screen and detect pre-cancers. The development of a noninvasive and accurate method for real-time screening and diagnosis of oral cavity lesions would have great potential to improve early detection of neoplastic changes, and thereby improve the quality of life and survival rates for persons developing carcinomas of the oral cavity.
Cervical cancer is the third most common cancer in women worldwide and the leading cause of cancer mortality in women in developing countries. The curable precursor to cervical cancer is cervical intra-epithelial neoplasia. In the U.S. over $6 billion are spent annually in the evaluation and treatment of low-grade precursor lesions. Approximately 50 million Pap smears are performed annually in the U.S. to screen for cervical cancer and its precursor. The National Cancer Institute estimates 6-7% of these tests to be abnormal. However, cervical cancer goes undetected in developing countries because of the cost of the tests and the lack of trained personnel and resources. In the U.S., resources are wasted on the evaluation and treatment of lesions that are not likely to progress to cancer.
Optical technologies offer the ability to image tissue with unprecedented spatial and temporal resolution using low-cost, portable devices. As such, optical technologies represent an ideal approach to imaging early neoplasia. Multiple in vivo optical imaging and spectroscopic modalities have been explored recently as diagnostic tools in medicine. These modalities include multi-spectral fluorescence imaging, multi-spectral reflectance imaging with unpolarized and polarized light, confocal microscopy, reflectance, and fluorescence spectroscopy. In the ultraviolet (UV) and visible regions of the spectrum, tissue reflectance spectra provide information about the wavelength dependent scattering of tissue as well as electronic absorption bands, primarily those of oxy- and deoxyhemoglobin. The most common naturally occurring fluorophores include the aromatic amino acids, the co-factors NAD(P)H and FAD, crosslinks associated with collagen and elastin, and porphyrins.
Furthermore, optical technologies may be used to complement existing pre-cancer treatments, such as chemoprevention. Chemoprevention refers to the use of chemical agents to prevent or to delay the development of cancer in healthy populations or patients with precancerous tissue changes. Despite their promise, chemoprevention studies have several inherent problems. One is that many patients hesitate to enroll in such trials because they require multiple biopsies throughout the period when the chemopreventive agent is given. Biopsies are processed to measure morphologic and biochemical changes associated with cancer progression and assess drug response. A second problem is that the biopsy process itself can interrupt the natural progression of the lesion. Many times these lesions are small enough that the biopsy is the cure; frequent biopsies make it difficult to accurately assess drug response. Thus, tools that non-destructively assess quantitative morphologic and biochemical changes that do not require biopsy could considerably improve chemoprevention studies.
Both screening and detection could be vastly improved by in vivo optical imaging technologies that improve the ability to recognize and delineate pre-cancerous lesions in the cervix with high sensitivity and specificity. A major challenge in implementing quantitative optical tools for widespread screening is to develop small, inexpensive imaging systems that provide both high sensitivity and high specificity for the biochemical and morphologic features of pre-cancer. A need therefore exists for small, inexpensive imaging systems that may enhance or replace traditional visual exam procedures to allow for more accurate identification of pre-cancerous lesions.